Hepatitis is a serious world-wide health problem. Approximately 200 million people are chronically infected with hepatitis B virus and large numbres of deaths are attributed to fulminant hepatitis, cirrhosis, and hepatocellular carcinoma. Although an effective subunit vaccine has been produced, limitations in supply and expense have prevented its global use. As an alternative, we are trying to construct a live recombinant hepatitis B vaccine. The gene for hepatitis B virus surface antigen has been engineered and inserted into the genome of vaccinia virus. The recombinant vaccinia virus is stable and expresses high levels of the hepatitis virus protein. The latter is glycosylated. assembled into particles and transported through the plasma membrane of infected cells. Rabbits, vaccinated with the recombinant virus, produce a high and sustained specific antibody response. Vaccination of chimpanzees resulted in priming of the immune system and protection against clinical hepatitis upon subsequent challenge with hepatitis B virus. Vaccinia virus recombinants that express higher levels of HBsAg have been constructed by using the promoter from a major structural protein of vaccinia virus and are being evaluated. Recent studies have indicated that the DNA sequence preceding the HBsAg gene, referred to as pre-S, is expressed by hepatitis B virus and contains immunologically dominant epitopes. A vaccinia virus recombinant that expresses the entire long open-reading-frame was constructed. Rabbits vaccinated with this recombinant produced antibodies to pre-S and S epitopes.